Age-related cataracts occur more frequently in women than in men of comparable age. It is believed that this is due to the loss of estrogen after menopause. Support for this hypothesis comes from epidemiological studies, which show that hormone replacement therapy reduces the risk of cataract, and from animal studies, which show that estradiol prevents TGF-beta-induced anterior subcapsular cataracts in ovariectomized rats. We extended the latter observation by testing whether estradiol protects against TGF-beta-induced cataracts in lenses from normal male and female rats. Our results showed that in the presence of low concentrations of TGF-beta2 (0.15 ng/ml), cultured male rat lenses developed twice as many cataract plaques as female rat lenses. Estradiol (10-8M) prevented cataracts in female lenses, but not male lenses. In parallel, the anterior subcapsular cataract marker, alpha-smooth muscle actin, was up regulated in both male and female rat lenses, but down regulated only in female lenses in the presence of estradiol. These findings suggest that there may be sex-specific differences in the levels of estrogen receptors. TGF-beta2-induced cataracts serve as a model of human anterior subcapsular cataracts and secondary cataracts, with many phenotypic and biochemical similarities. The results of our study suggest that estradiol could be a therapeutic option, although, the sex-related response must first be tested in human lenses.